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Ferristatin II, an Iron Uptake Inhibitor, Exerts Neuroprotection against Traumatic Brain Injury via Suppressing Ferroptosis
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2022-02-10 , DOI: 10.1021/acschemneuro.1c00819 Ying Cheng 1 , Wenhao Qu 2 , Jing Li 1 , Bowen Jia 1 , Yiting Song 1 , Liyu Wang 1 , Tongyu Rui 1 , Qianqian Li 3 , Chengliang Luo 1
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2022-02-10 , DOI: 10.1021/acschemneuro.1c00819 Ying Cheng 1 , Wenhao Qu 2 , Jing Li 1 , Bowen Jia 1 , Yiting Song 1 , Liyu Wang 1 , Tongyu Rui 1 , Qianqian Li 3 , Chengliang Luo 1
Affiliation
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As a specific ferroptosis marker, transferrin receptor 1 (TfR1) expression is increased following traumatic brain injury (TBI), but the precise role of TfR1 in TBI-induced ferroptosis and neurodegeneration remains to be determined. To further identify more potent ferroptosis inhibitors and effective targets for treating TBI, our study aims at investigating the effects of TfR1 on ferroptosis in a mouse TBI model using ferristatin II (an iron uptake and TfR1 inhibitor). The effect of ferristatin II was first verified in the HT-22 cell line in vitro and showed antiferroptotic action when exposed to ferric citrate (FAC), which is in parallel with the results obtained from the positive controls, including deferoxamine (DFO) and liproxstatin-1 (Lip-1). In vivo, ferristatin II administration reduced the expression of TfR1 at 12 h after TBI, and immunofluorescence experiments further confirmed that this decreased TfR1-positive cells were neurons. Importantly, ferristatin II suppressed TBI-induced iron homeostatic imbalance by decreasing the content of Fe (III) and iron-positive deposits and reversed the expression of iron homeostasis-related proteins. Moreover, ferristatin II attenuated TBI-induced lipid peroxidation by reversing the expression of lipid peroxidative genes and proteins, as well as the increase in malondialdehyde (MDA) level following TBI. Finally, ferristatin II alleviated TBI-induced neuronal injury and neurodegeneration, as detected by staining with Nissl and Fluoro-Jade B, thereby exerting a neuroprotective effect. In summary, these data indicated that ferristatin II might be a potential strategy to restrain ferroptosis and develop novel therapeutic agents against TBI.
中文翻译：
铁摄取抑制剂 Ferristatin II 通过抑制铁死亡发挥神经保护作用以防止创伤性脑损伤
作为特定的铁死亡标志物，转铁蛋白受体 1 (TfR1) 的表达在创伤性脑损伤 (TBI) 后增加，但 TfR1 在 TBI 诱导的铁死亡和神经退行性变中的确切作用仍有待确定。为了进一步确定更有效的铁死亡抑制剂和治疗 TBI 的有效靶点，我们的研究旨在使用 ferristatin II（一种铁摄取和 TfR1 抑制剂）研究 TfR1 对小鼠 TBI 模型中铁死亡的影响。ferristatin II 的作用首先在体外HT-22 细胞系中得到验证，当暴露于柠檬酸铁 (FAC) 时显示出抗铁死亡作用，这与阳性对照（包括去铁胺 (DFO) 和利普他汀）获得的结果平行-1（唇 1）。体内，ferristatin II 给药在 TBI 后 12 小时降低了 TfR1 的表达，免疫荧光实验进一步证实了这种降低的 TfR1 阳性细胞是神经元。重要的是，ferristatin II 通过降低 Fe (III) 和铁阳性沉积物的含量来抑制 TBI 诱导的铁稳态失衡，并逆转铁稳态相关蛋白的表达。此外，ferristatin II 通过逆转脂质过氧化基因和蛋白质的表达以及 TBI 后丙二醛 (MDA) 水平的增加来减弱 TBI 诱导的脂质过氧化。最后，通过 Nissl 和 Fluoro-Jade B 染色检测，ferristatin II 减轻了 TBI 引起的神经元损伤和神经变性，从而发挥神经保护作用。总之，
更新日期：2022-02-10
中文翻译：
铁摄取抑制剂 Ferristatin II 通过抑制铁死亡发挥神经保护作用以防止创伤性脑损伤
作为特定的铁死亡标志物，转铁蛋白受体 1 (TfR1) 的表达在创伤性脑损伤 (TBI) 后增加，但 TfR1 在 TBI 诱导的铁死亡和神经退行性变中的确切作用仍有待确定。为了进一步确定更有效的铁死亡抑制剂和治疗 TBI 的有效靶点，我们的研究旨在使用 ferristatin II（一种铁摄取和 TfR1 抑制剂）研究 TfR1 对小鼠 TBI 模型中铁死亡的影响。ferristatin II 的作用首先在体外HT-22 细胞系中得到验证，当暴露于柠檬酸铁 (FAC) 时显示出抗铁死亡作用，这与阳性对照（包括去铁胺 (DFO) 和利普他汀）获得的结果平行-1（唇 1）。体内，ferristatin II 给药在 TBI 后 12 小时降低了 TfR1 的表达，免疫荧光实验进一步证实了这种降低的 TfR1 阳性细胞是神经元。重要的是，ferristatin II 通过降低 Fe (III) 和铁阳性沉积物的含量来抑制 TBI 诱导的铁稳态失衡，并逆转铁稳态相关蛋白的表达。此外，ferristatin II 通过逆转脂质过氧化基因和蛋白质的表达以及 TBI 后丙二醛 (MDA) 水平的增加来减弱 TBI 诱导的脂质过氧化。最后，通过 Nissl 和 Fluoro-Jade B 染色检测，ferristatin II 减轻了 TBI 引起的神经元损伤和神经变性，从而发挥神经保护作用。总之，
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